Use of thiazolidinedione derivatives in the treatment of anovulation, hyperandrogenism and hirsutism

ABSTRACT

The present invention provides methods of using thiazolidinone derivatives to treat anovulation, hyperandrogenism and hirsutism.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of Ser. No. 08/868,608, filed Jun. 4,1997, which is a continuation-in-part of 08/856,987, filed May 15, 1997,now U.S Pat. No. 5,874,454, which is a continuation-in-part of08/763,286, filed on Dec. 10, 1996, now abandoned which is a divisionalof Ser. No. 08/469,398, filed Jun. 6, 1995, now U.S. Pat. No. 5,602,133,which is a divisional of Ser. No. 08/292,585, filed Aug. 23, 1994, nowU.S. Pat. No. 5,457,109, which is a continuation-in-part of Ser. No.08/122,251, filed Sep. 15, 1993, now abandoned.

FIELD OF THE INVENTION

The present invention pertains to a number of compounds which can beused to treat anovulation, hyperandrogenism and hirsutism.

BACKGROUND OF THE INVENTION

Diabetes is one of the most prevalent chronic disorders worldwide withsignificant personal and financial costs for patients and theirfamilies, as well as for society. Different types of diabetes exist withdistinct etiologies and pathogeneses. For example, diabetes mellitus isa disorder of carbohydrate metabolism, characterized by hyperglycemiaand glycosuria and resulting from inadequate production or utilizationof insulin.

Noninsulin-dependent diabetes mellitus (NIDDM), or otherwise referred toas Type II diabetes, is the form of diabetes mellitus which occurspredominantly in adults in whom adequate production of insulin isavailable for use, yet a defect exists in insulin-mediated utilizationand metabolism of glucose in peripheral tissues. Overt NIDDM ischaracterized by three major metabolic abnormalities: resistance toinsulin-mediated glucose disposal, impairment of nutrient-stimulatedinsulin secretion, and overproduction of glucose by the liver. It hasbeen shown that for some people with diabetes a genetic predispositionresults in a mutation in the gene(s) coding for insulin and/or theinsulin receptor and/or insulin-mediated signal transduction factor(s),thereby resulting in ineffective insulin and/or insulin-mediated effectsthus impairing the utilization or metabolism of glucose.

Reports indicate that insulin secretion is often enhanced early-on,presumably as compensation for the insulin resistance. People whoactually develop NIDDM appear to do so because their B-cells eventuallyfail to maintain sufficient insulin secretion to compensate for theinsulin resistance. Mechanisms responsible for the B-cell failure havenot been identified, but may be related to the chronic demands placed onthe B-cells by peripheral insulin resistance and/or to the effects ofhyperglycemia to impair B-cell function. The B-cell failure could alsooccur as an independent, inherent defect in "pre-diabetic" individuals.

NIDDM often develops from certain at risk populations, one suchpopulation is individuals with polycystic ovary syndrome (PCOS). PCOS isthe most common endocrine disorder in women of reproductive age. Thissyndrome is characterized by hyperandrogenism and disorderedgonadotropin secretion producing oligo- or anovulation. Recentprevalence estimates suggest that 5-10% of women between 18-44 years ofage (about 5 million women, according to the 1990 census) have thefull-blown syndrome of hyperandrogenism, chronic anovulation, andpolycystic ovaries. Despite more than 50 years since its originaldescription, the etiology of the syndrome remains unclear. Thebiochemical profile, ovarian morphology, and clinical features arenon-specific; hence, the diagnosis remains one of exclusion ofdisorders, such as androgen-secreting tumors, Cushing's Syndrome, andlate-onset congenital adrenal hyperplasia.

PCOS is associated with profound insulin resistance resulting insubstantial hyperinsulinemia. As a result of their insulin resistance,PCOS women are at increased risk to develop NIDDM. Hirsutism, acne, andalopecia, which are commonly found in PCOS women, are clinicalmanifestations of hyperandrogenism. Menstrual disturbances andinfertility are the result of ovulatory dysfunction related to thedisordered gonadotropin secretion. Androgen excess, probably by eventualconversion of androgens to estrogen, also plays an important role indisrupting gonadotropin release in PCOS.

There are two leading hypotheses for the association between PCOS andinsulin resistance: 1) androgens produce insulin resistance or 2)hyperinsulinemia produces hyperandrogenism. In support of the firsthypothesis, synthetic androgen administration can increase insulinlevels in women. However, in PCOS women with acanthosis nigricans (whichis a marker for insulin resistance), oophorectomy lowers testosteronelevels but does not alter insulin resistance. Further, long-acting GnRHagonist treatment in PCOS women decreases plasma testosterone andandrostenedione levels into the normal female range, but does not alterglucose tolerance, insulin levels, or insulin action. Thus, althoughcertain synthetic androgens may have a modest effect on insulinsensitivity, natural androgens do not produce insulin resistance of themagnitude found in PCOS.

In contrast, there are several lines of evidence that support thealternative hypothesis that hyperinsulinemia produces hyperandrogenism.First, extreme insulin resistance of a variety of etiologies, rangingfrom insulin receptor mutations to autoimmune insulin resistance, isassociated with ovarian hyperandrogenism. Second, insulin can directlystimulate ovarian androgen secretion in vitro and in vivo in PCOS women.Finally, decreasing insulin levels for 10 days with diazoxide results ina significant decrease in testosterone levels in PCOS women. Insulindoes not alter gonadotropin release but rather appears to act directlyon the ovary. However, these actions of insulin are not observed innormal ovulatory women, suggesting that polycystic ovarian changes arenecessary for such insulin effects to be manifested.

Insulin resistance in PCOS is secondary to a marked decrease in insulinreceptor-mediated signal transduction and a modest, but significant,decrease in adipocyte GLUT4 content. In many PCOS women, the decrease ininsulin receptor signaling is the result of intrinsic abnormalities ininsulin receptor phosphorylation. The magnitude of insulin resistance inPCOS is similar to that in NIDDM and in obesity. However, the cellularmechanisms of insulin resistance appear to differ in PCOS compared tothese other common insulin-resistant states. The shift to the right inthe insulin dose-response curve for adipocyte glucose uptake is muchmore striking in PCOS than in obesity. Further, decreases in adipocyteinsulin sensitivity and responsiveness are significantly correlated withhyperinsulinemia, glycemia, and/or obesity in individuals with NIDDM orobesity, whereas insulin resistance is independent of these parametersin PCOS. Finally, no persistent abnormalities in insulin receptorautophosphorylation have been identified in NIDDM or obesity.

NIDDM also develops from the at risk population of individuals withgestational diabetes mellitus (GDM). Pregnancy normally is associatedwith progressive resistance to insulin-mediated glucose disposal. Infact, insulin sensitivity is lower during late pregnancy than in nearlyall other physiological conditions. The insulin resistance is thought tobe mediated in large part by the effects of circulating hormones such asplacental lactogen, progesterone, and cortisol, all of which areelevated during pregnancy. In the face of the insulin resistance,pancreatic B-cell responsiveness to glucose normally increases nearly3-fold by late pregnancy, a response that serves to minimize the effectof insulin resistance on circulating glucose levels. Thus, pregnancyprovides a major "stress-test" of the capacity for B-cells to compensatefor insulin resistance.

Studies of insulin action and B-cell function during pregnancy indicatethat, during the third trimester, women with mild-moderate GDM have thesame degree of insulin resistance as do non-diabetic pregnant women.However, studies during the second trimester and after pregnancyindicate that women with GDM are somewhat insulin resistant compared towomen who maintain normal glucose tolerance during pregnancy. Takentogether, the available data indicate that pancreatic B-cells of womenwho develop GDM may encounter two types of insulin resistance: 1)mild-moderate, underlying, and perhaps genetic insulin resistance thatis present even when the women are not pregnant; and 2) the marked,physiological (probably hormonally-mediated) insulin resistance thatoccurs during pregnancy in all women. Data indicate that the mainfeature which distinguishes women with GDM from normal pregnant womenduring the third trimester, when all women are insulin resistant, ispancreatic B-cell function. Most women develop GDM because theirpancreatic B-cells are unable to maintain enhanced insulin secretion inthe face of insulin resistance. That inability is very similar to theB-cell defect which has been observed in longitudinal studies ofpatients who develop NIDDM, a fact which may explain why women with GDMare at such high risk for NIDDM: GDM identifies women whose B-cells willdecompensate when faced with severe or chronic insulin resistance.

Other populations thought to be at risk for developing NIDDM are personswith Syndrome X; persons with concomitant hyperinsulinemia; persons withinsulin resistance characterized by hyperinsulinemia and by failure torespond to exogenous insulin; and persons with abnormal insulin and/orevidence of glucose disorders associated with excess circulatingglucocorticoids, growth hormone, catecholamines, glucagon, parathyroidhormone, and other insulin-resistant conditions.

Failure to treat NIDDM can result in mortality due to cardiovasculardisease and in other diabetic complications including retinopathy,nephropathy, and peripheral neuropathy. For many years treatment ofNIDDM has involved a program aimed at lowering blood sugar with acombination of diet and exercise. Alternatively, treatment of NIDDMinvolved oral hypoglycemic agents, such as sulfonylureas alone or incombination with insulin injections. Recently, alpha-glucosidaseinhibitors, such as a carboys, have been shown to be effective inreducing the postprandial rise in blood glucose (Lefevre et al., Drugs,1992;44:29-38). In Europe and Canada another treatment used primarily inobese diabetics is metformin, a biguanide.

In any event, what is required is a method of treating at riskpopulations such as those with PCOS and GDM in order to prevent or delaythe onset of NIDDM thereby bringing relief of symptoms, improving thequality of life, preventing acute and long-term complications, reducingmortality and treating accompanying disorders of the populations at riskfor NIDDM. The methods of using the disclosed compounds for treating atrisk populations with conditions such as PCOS and GDM to prevent ordelay the onset of NIDDM as taught herein meet these objectives.

The compounds of the present invention, and methods of making thecompounds, are known and some of these are disclosed in U.S. Pat. Nos.5,223,522 issued Jun. 29, 1993; U.S. Pat. No. 5,132,317 issued Jul. 12,1992; U.S. Pat. No. 5,120,754 issued Jun. 9, 1992; U.S. Pat. No.5,061,717 issued Oct. 29, 1991; U.S. Pat. No. 4,897,405 issued Jan. 30,1990; U.S. Pat. No. 4,873,255 issued Oct. 10, 1989; U.S. Pat. No.4,687,777 issued Aug. 18, 1987; U.S. Pat. No. 4,572,912 issued Feb. 25,1986; U.S. Pat. No. 4,287,200 issued Sept. 1, 1981; U.S. Pat. No.5,002,953, issued Mar. 26, 1991; U.S. Pat. Nos. 4,340,605; 4,438,141;4,444,779; 4,461, 902; 4,703,052; 4,725,610; 4,897,393; 4,918,091;4,948,900; 5,194,443; 5,232,925; and 5,260,445; WO 91/07107; WO92/02520; WO 94/01433; WO 89/08651; and JP Kokai 69383/92. The compoundsdisclosed in these issued patents and applications are useful astherapeutic agents for the treatment of diabetes, hyperglycemia,hypercholesterolemia, and hyperlipidemia. The teachings of these issuedpatents and applications are incorporated herein by reference.

Regarding prevention of NIDDM, there has been one disclosure of thisconcept using a sulfonylurea as a treatment, but this concept is nothighly regarded in the scientific community because prolonged treatmentwith sulfonylureas can reduce insulin secretion by destroying thepancreatic beta cells. Moreover, sulfonylureas can cause clinicallysevere hypoglycemia. The concept of using a biguanide, such asmetformin, has also been disclosed.

There is no disclosure in the above-identified references to suggest theuse of the compounds identified in this present application in thetreatment of at risk populations such as those with PCOS or GDM in orderto prevent or delay the onset of NIDDM and complications resultingtherefrom.

SUMMARY OF THE INVENTION

In one embodiment of this invention, a method is disclosed for thetreatment of PCOS in order to prevent or delay the onset of NIDDM.Improvement in insulin sensitivity by treatment with the compounds ofthe following formulas will reduce fasting insulin levels, therebyresulting in decreased androgen production and biologic availability inPCOS women. Decreasing androgen levels will improve the clinicalsymptoms of androgen excess and the anovulation commonly found in PCOSwomen.

In another embodiment of this invention, a method is disclosed for thetreatment of GDM. Improvement in whole-body insulin sensitivity bytreatment with the compounds of the following formulas will reduce therate of B-cell decomposition and delay or prevent the development ofNIDDM in women with GDM. The compounds can also be applied to formergestational diabetic women to delay or prevent NIDDM and its long-termcomplications. As agents having the aforementioned effects, thecompounds of the following formulas are useful in treating individualsto prevent or delay the onset of NIDDM.

In another embodiment of the present invention is a method for treatingpopulation states, other than those with PCOS or GDM, who are at riskfor developing NIDDM. Other populations thought to be at risk fordeveloping NIDDM are persons with Syndrome X; persons with concomitanthyperinsulinemia; persons with insulin resistance characterized byhyperinsulinemia and by failure to respond to exogenous insulin; andpersons with abnormal insulin and/or evidence of glucose disordersassociated with excess circulating glucocorticoids, growth hormone,catecholamines, glucagon, parathyroid hormone, and otherinsulin-resistant conditions. Treatment of the above populations withthe compounds of the following formulas will prevent or delay the onsetof NIDDM.

Accordingly, the present invention is the use of compounds of Formula I##STR1## herein R¹ and R² are the same or different and each representsa hydrogen atom or a C₁ -C₅ alkyl group;

R³ represents a hydrogen atom, a C₁ -C₆ aliphatic acyl group, analicyclic acyl group, an aromatic acyl group, a heterocyclic acyl group,an araliphatic acyl group, a (C₁ -C₆ alkoxy)carbonyl group, or anaralkyloxycarbonyl group;

R⁴ and R⁵ are the same or different and each represents a hydrogen atom,a C₁ -C₅ alkyl group or a C₁ -C₅ alkoxy group, or R⁴ and R⁵ togetherrepresent a C₁ -C₄ alkylenedioxy group;

n is 1,2, or3;

W represents the --CH₂ --, >CO, or CH--OR⁶ group (in which R⁶ representsany one of the atoms or groups defined for R³ and may be the same as ordifferent from R³); and

Y and Z are the same or different and each represents an oxygen atom oran imino (INH) group;

and pharmaceutically acceptable salts thereof.

The present invention is also the use of compounds of the Formula II##STR2## wherein R₁₁ is substituted or unsubstituted alkyl, alkoxy,cycloalkyl, phenylalkyl, phenyl, aromatic acyl group, a 5- or 6-memberedheterocyclic group including 1 or 2 heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur, or a group of the formula##STR3## wherein R₁₃ and R₁₄ are the same or different and each is loweralkyl or R₁₃ and R₁₄ are combined to each other either directly or asinterrupted by a heteroatom selected from the group consisting ofnitrogen, oxygen, and sulfur to form a 5- or 6-membered ring;

wherein R₁₂ means a bond or a lower alkylene group; and

wherein L₁ and L₂ are the same or different and each is hydrogen orlower alkyl or L₁ and L₂ are combined to form an alkylene group; or apharmaceutically acceptable salt thereof.

The present invention is also the use of compounds of the Formula III##STR4## wherein R₁₅ and R₁₆ are independently hydrogen, lower alkylcontaining 1 to 6 carbon atoms, alkoxy containing 1 to 6 carbon atoms,halogen, ethynyl, nitrile, methylthio, trifluoromethyl, vinyl, nitro, orhalogen substituted benzyloxy; n is 0 to 4 and the pharmaceuticallyacceptable salts thereof.

The present invention is also directed to the use of compounds of theFormula IV ##STR5## wherein the dotted line represents a bond or nobond; V is --CH═CH--, --N═CH--, --CH═N-- or S;

D is CH₂, CHOH, CO, C═NOR₁₇ or CH═CH;

X is S, O, NR₁₈, --CH═N or --N═CH;

Y is CH or N;

Z is hydrogen, (C₁ -C₇) alkyl, (C₃ -C₇)cycloalkyl, phenyl, naphthyl,pyridyl, furyl, thienyl, or phenyl mono- or disubstituted with the sameor different groups which are (C₁ -C₃)alkyl, trifluoromethyl, (C₁-C₃)alkoxy, fluoro, chloro, or bromo;

Z₁ is hydrogen or (C₁ -C₃)alkyl;

R₁₇ and R₁₈ are each independently hydrogen or methyl; and n is 1, 2, or3;

the pharmaceutically acceptable cationic salts thereof; and thepharmaceutically acceptable acid addition salts thereof when thecompound contains a basic nitrogen.

The present invention is also directed to the use of compounds of theFormula V ##STR6## wherein the dotted line represents a bond or no bond;A and B are each independently CH or N, with the proviso that when A orB is N, the other is CH;

X₁ is S, SO, SO₂, CH₂, CHOH, or CO;

n is 0 or 1;

Y₁ is CHR₂₀ or R₂₁, with the proviso that when n is 1 and Y₁ is NR₂₁, X₁is SO₂ or CO;

Z₂ is CHR₂₂, CH₂ CH₂, CH═CH, ##STR7## OCH₂, SCH₂, SOCH₂ or SO₂ CH₂ ;R₁₉, R₂₀, R₂₁, and R₂₂ are each independently hydrogen or methyl; and

X₂ and X₃ are each independently hydrogen, methyl, trifluoromethyl,phenyl, benzyl, hydroxy, methoxy, phenoxy, benzyloxy, bromo, chloro, orfluoro;

a pharmaceutically acceptable cationic salt thereof; or apharmaceutically acceptable acid addition salt thereof when A or B is N.

The present invention also relates to the use of compounds of theFormula VI ##STR8## or a pharmaceutically acceptable salt thereofwherein R₂₃ is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbonatoms, phenyl or mono- or di-substituted phenyl wherein saidsubstituents are independently alkyl of 1 to 6 carbon atoms, alkoxy of 1to 3 carbon atoms, halogen, or trifluoromethyl.

The present invention also provides the use of a compound of Formula VII##STR9## or a tautomeric form thereof and/or a pharmaceuticallyacceptable salt thereof, and/or a pharmaceutically acceptable solvatethereof, wherein:

A₂ represents an alkyl group, a substituted or unsubstituted aryl group,or an aralkyl group wherein the alkylene or the aryl moiety may besubstituted or unsubstituted;

A₃ represents a benzene ring having in total up to 3 optionalsubstituents;

R₂₄ represents a hydrogen atom, an alkyl group, an acyl group, anaralkyl group wherein the alkyl or the aryl moiety may be substituted orunsubstituted, or a substituted or unsubstituted aryl group; or A₂together with R₂₄ represents substituted or unsubstituted C₂₋₃polymethylene group, optional substituents for the polymethylene groupbeing selected from alkyl or aryl or adjacent substituents together withthe methylene carbon atoms to which they are attached form a substitutedor unsubstituted phenylene group;

R₂₅ and R₂₆ each represent hydrogen, or R₂₅ and R₂₆ together represent abond; X₄ represents O or S; and

n represents an integer in the range of from 2 to 6.

The present invention also provides the use of a compound of FormulaVIII ##STR10## or a tautomeric form thereof and/or a pharmaceuticallyacceptable salt thereof, and/or a pharmaceutically acceptable solvatetherefor, wherein:

R₂₇ and R₂₈ each independently represent an alkyl group, a substitutedor unsubstituted aryl group, or an aralkyl group being substituted orunsubstituted in the aryl or alkyl moiety; or R₂₇ together with R₂₈represents a linking group, the linking group consisting of anoptionally substituted methylene group and either a further optionallysubstituted methylene group or an O or S atom, optional substituents forthe said methylene groups being selected from alkyl-, aryl, or aralkyl,or substituents of adjacent methylene groups together with the carbonatoms to which they are attached form a substituted or unsubstitutedphenylene group;

R₂₉ and R₃₀ each represent hydrogen, or R₂₉ and R₃₀ together represent abond;

A₄ represents a benzene ring having in total up to 3 optionalsubstituents;

X₅ represents O or S; and

n represents an integer in the range of from 2 to 6.

The present invention also provides the use of a compound of Formula IX##STR11## or a tautomeric form thereof and/or a pharmaceuticallyacceptable salt thereof, and/or a pharmaceutically acceptable solvatethereof, wherein:

A₅ represents a substituted or unsubstituted aromatic heterocyclylgroup;

A₆ represents a benzene ring having in total up to 5 substituents;

X₆ represents O,S, or NR₃₂ wherein R₃₂ represents a hydrogen atom, analkyl group, an acyl group, an aralkyl group, wherein the aryl moietymay be substituted or unsubstituted, or a substituted or unsubstitutedaryl group;

Y2 represents O or S;

R₃₁ represents an alkyl, aralkyl, or aryl group; and

n represents an integer in the range of from 2 to 6.

Suitable aromatic heterocyclyl groups include substituted orunsubstituted, single or fused ring aromatic heterocyclyl groupscomprising up to 4 hetero atoms in each ring selected from oxygen,sulphur, or nitrogen.

Favored aromatic heterocyclyl groups include substituted orunsubstituted single ring aromatic heterocyclyl groups having 4 to 7ring atoms, preferably 5 or 6 ring atoms.

In particular, the aromatic heterocyclyl group comprises 1, 2, or 3heteroatoms, especially 1 or 2, selected from oxygen, sulphur, ornitrogen.

Suitable values for A₅ when it represents a 5-membered aromaticheterocyclyl group include thiazolyl and oxazoyl, especially oxazoyl.

Suitable values for A₅ when it represents a 6-membered aromaticheterocyclyl group include pyridyl or pyrimidinyl.

Suitable R₃₁ represents an alkyl group, in particular a C₁₋₆ alkylgroup, for example a methyl group. Preferably, A₅ represents a moiety offormula (a), (b), or (c): ##STR12## wherein: R₃₃ and R₃₄ eachindependently represents a hydrogen atom, an alkyl group, or asubstituted or unsubstituted aryl group or when R₃₃ and R₃₄ are eachattached to adjacent carbon atoms, then R₃₃ and R₃₄ together with thecarbon atoms to which they are attached form a benzene ring wherein eachcarbon atom represented by R₃₃ and R₃₄ together may be substituted orunsubstituted; and in the moiety of Formula (a), X₇ represents oxygen orsulphur.

In one favored aspect R₃₃ and R₃₄ together represent a moiety of Formula(d): ##STR13## wherein R₃₅ and R₃₆ each independently representhydrogen, halogen, substituted or unsubstituted alkyl, or alkoxy.

The present invention also provides for the use of compounds for FormulaX ##STR14## or a tautomeric form thereof and/or a pharmaceuticallyacceptable salt thereof, and/or a pharmaceutically acceptable solvatethereof, wherein:

A₇ represents a substituted or unsubstituted aryl group;

A₈ represents a benzene ring having in total up to 5 substituents;

X₈ represents O,S, or NR₃₉ wherein R₃₉ represents a hydrogen atom, analkyl group, an acyl group, an aralkyl group, wherein the aryl moietymay be substituted or unsubstituted, or a substituted or unsubstitutedaryl group;

Y₃ represents O or S;

R₃₇ represents hydrogen;

R₃₈ represents hydrogen or an alkyl, aralkyl, or aryl group or R₃₇together with R₃₈ represents a bond; and n represents an integer in therange of from 2 to 6.

A still further embodiment of the present invention is the use of apharmaceutical composition for administering an effective amount of acompound of the preceding Formulas I through X along with apharmaceutically acceptable carrier in unit dosage form in the treatmentmethods mentioned above.

The present invention also provides a method of treating anovulation,the method comprising administering to a patient suffering fromanovulation a therapeutically effective amount of(+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione(Troglitazone).

The present invention also provides a method of treating anovulation,the method comprising administering to a patient suffering fromanovulation a therapeutically effective amount of5-[p-[1-methylcyclohexyl)methoxyl]benzyl]-2,4-thiazolidinedione(Ciglitazone),5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione(Pioglitazone),5-[p-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]benzyl]-2,4-thiazolidinedione(Darglitazone), or5-[[(2R)-2-benzyl-6-chromanyl]methyl]-2,4-thiazolidinedione(Englitazone).

The present invention also provides a method of treating anovulation,the method comprising administering to a patient suffering fromanovulation a therapeutically effective amount of5-(4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl)-2,4-thiazolidine(Rosiglitazone).

The present invention also provides a method of treatinghyperandrogensim, the method comprising administering to a patientsuffering from hyperandrogensim a therapeutically effective amount of(+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione(Troglitazone).

The present invention also provides a method of treatinghyperandrogensim, the method comprising administering to a patientsuffering from hyperandrogensim a therapeutically effective amount of5-[p-[1-methylcyclohexyl)methoxyl]benzyl]-2,4-thiazolidinedione(Ciglitazone),5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione(Pioglitazone),5-[p-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]benzyl]-2,4-thiazolidinedione(Darglitazone), or5-[[(2R)-2-benzyl-6-chromanyl]methyl]-2,4-thiazolidinedione(Englitazone).

The present invention also provides a method of treatinghyperandrogensim, the method comprising administering to a patientsuffering from hyperandrogensim a therapeutically effective amount of5-(4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl)-2,4-thiazolidine(Rosiglitazone).

The present invention also provides a method of treating hirsutism, themethod comprising administering to a patient suffering from hirsutism atherapeutically effective amount of(+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione(Troglitazone).

The present invention also provides a method of treating hirsutism, themethod comprising administering to a patient suffering from hirsutism atherapeutically effective amount of5-[p-[1-methylcyclohexyl)methoxyl]benzyl]-2,4-thiazolidinedione(Ciglitazone),5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione(Pioglitazone),5-[p-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]benzyl]-2,4-thiazolidinedione(Darglitazone), or5-[[(2R)-2-benzyl-6-chromanyl]methyl]-2,4-thiazolidinedione(Englitazone).

The present invention also provides a method of treating hirsutism, themethod comprising administering to a patient suffering from hirsutism atherapeutically effective amount of5-(4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl)-2,4-thiazolidine(Rosiglitazone).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The compounds used in the treatment methods of the invention, which are5-[4-(chromoanalkoxy)benzyl]thiazolidene derivatives, may be representedby the Formulas (Ia), (Ib), and (Ic) ##STR15## (in which R¹, R², R³, R⁴,R⁵, R⁶, n, Y, and Z are as defined above) and include pharmaceuticallyacceptable salts thereof.

In the compounds of the invention, where R¹ or R² represents an alkylgroup, this may be a straight or branched chain alkyl group having from1 to 5 carbon atoms and is preferably a primary or secondary alkylgroup, for example the methyl, ethyl, propyl, isopropyl, butyl,isobutyl, pentyl, or isopentyl group.

Where R³, R⁶, or R^(6') represents an aliphatic acyl group, thispreferably has from 1to 6 carbon atoms and may include one or morecarbon-carbon double or triple bonds. Examples of such groups includethe formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl,acryloyl, methacryloyl, and crotonyl groups.

Where R³, R⁶, or R^(6') represents an alicyclic acyl group, it ispreferably a cyclopentanecarbonyl, cyclohexanecarbonyl, orcycloheptanecarbonyl group.

Where R³, R⁶, or R^(6') represents an aromatic acyl group, the aromaticmoiety thereof may optionally have one or more substituents (forexample, nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl, orhydroxy substituents); examples of such aromatic acyl groups includedthe benzoyl, p-nitrobenzoyl, m-fluorobenzoyl, o-chlorobenzoyl,p-aminobenzoyl, m-(dimethylamino)benzoyl, o-methoxybenzoyl,3,4-dichlorobenzoyl, 3,5-di-t-butyl-4-hydroxybenzoyl, and 1-naphthoylgroups.

Where R³, R⁶, or R^(6') represents a heterocyclic acyl group, theheterocyclic moiety thereof preferably has one or more, preferably one,oxygen, sulfur, or nitrogen hetero atoms and has from 4 to 7 ring atoms;examples of such heterocyclic acyl groups include the 2-furoyl,3-thenoyl, 3-pyridinecarbonyl (nicotinoyl), and 4-pyridinecarbonylgroups.

Where R³, R⁶, or R^(6') represents an araliphatic acyl group, thealiphatic moiety thereof may optionally have one or more carbon-carbondouble or triple bonds and the aryl moiety thereof may optionally haveone or more substituents (for example, nitro, amino, alkylamino,dialkylamino, alkoxy, halo, alkyl, or hydroxy substituents); examples ofsuch araliphatic acyl groups include the phenylacetyl,p-chlorophenylacetyl, phenylpropionyl, and cinnamoyl groups.

Where R³, R⁶, or R^(6') represents a (C₁ -C₆ alkoxy)carbonyl group, thealkyl moiety thereof may be any one of those alkyl groups as defined forR¹ and R², but is preferably a methyl or ethyl group, and thealkoxycarbonyl group represented by R³, R⁶, or R^(6') is thereforepreferably a methoxycarbonyl or ethoxycarbonyl group.

Where R³, R⁶, or R^(6') represents an aralkyloxycarbonyl group, thearalkyl moiety thereof may be any one of those included within thearaliphatic acyl group represented by R³, R⁶, or R^(6'), but ispreferably a benzyloxycarbonyl group.

Where R⁴ and R⁵ represent alkyl groups, they may be the same ordifferent and may be straight or branched chain alkyl groups. Theypreferably have from 1 to 5 carbon atoms and examples include themethyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, andisopentyl groups.

Where R⁴ and R⁵ represent alkoxy groups, these may be the same ordifferent and may be straight or branched chain groups, preferablyhaving from 1 to 4 carbon atoms. Examples include the methoxy, ethoxy,propoxy, isopropoxy, and butoxy groups. Alternatively, R⁴ and R⁵ maytogether represent a C₁ -C₄ alkylenedioxy group, more preferably amethylenedioxy or ethylenedioxy group.

Preferred classes of compounds of Formula I are as follows:

(1) Compounds in which R³ represents a hydrogen atom, a C₁ -C₆ aliphaticacyl group, an aromatic acyl group, or a heterocyclic acyl group.

(2) Compounds in which Y represents an oxygen atom; R¹ and R² are thesame or different and each represents a hydrogen atom or a C₁ -C₅ alkylgroup; R³ represents a hydrogen atom, a C₁ -C₆ aliphatic acyl group, anaromatic acyl group, or a pyridinecarbonyl group; and R⁴ and R⁵ are thesame or different and each represents a hydrogen atom, a C₁ -C₅ alkylgroup, or a C₁ or C₂ alkoxy group.

(3) Compounds as defined in (2) above, in which: R¹, R², R⁴, and R⁵ arethe same or different and each represents a hydrogen atom or a C₁ -C₅alkyl group; n is 1 or 2; and W represents the --CH₂ -- or >CO group.

(4) Compounds as defined in (3) above, in which R³ represents a hydrogenatom, a C₁ -C₅ aliphatic acyl group, a benzoyl group, or a nicotinylgroup.

(5) Compounds as defined in (4) above, in which: R¹ and R⁴ are the sameor different and each represents a C₁ -C₅ alkyl group; R² and R⁵ are thesame or different and each represents the hydrogen atom or the methylgroup; and R³ represents a hydrogen atom or a C₁ -C₄ aliphatic acylgroup.

(6) Compounds in which: W represents the --CH₂ -- or >CO group; Y and Zboth represent oxygen atoms; n is 1 or 2; R¹ and R⁴ are the same ordifferent and each represents a C₁ -C₄ alkyl group; R² and R⁵ are thesame or different and each represents the hydrogen atom or the methylgroup; and R³ represents a hydrogen atom or a C₁ -C₄ aliphatic acylgroup.

(7) Compounds as defined in (6) above, in which n is 1.

(8) Compounds as defined in (6) or (7) above, in which W represents the--CH₂ -- group.

Preferred compounds among the compounds of Formula I are those wherein:

R¹ is a C₁ -C₄ alkyl group, more preferably a methyl or isobutyl group,most preferably a methyl group;

R² is a hydrogen atom or a C₁ -C₄ alkyl group, preferably a hydrogenatom, or a methyl or isopropyl group, more preferably a hydrogen atom ora methyl group, most preferably a methyl group;

R³ is a hydrogen atom, a C₁ -C₄ aliphatic acyl group, an aromatic acylgroup or a pyridinecarbonyl group, preferably a hydrogen atom, or anacetyl, butyryl, benzoyl, or nicotinyl group, more preferably a hydrogenatom or an acetyl, butyryl or benzoyl group, most preferably a hydrogenatom or an acetyl group;

R⁴ is a hydrogen atom, a C₁ -C₄ alkyl group or a C₁ or C₂ alkoxy group,preferably a methyl, isopropyl, t-butyl, or methoxy group, morepreferably a methyl or t-butyl group, most preferably a methyl group;

R⁵ is a hydrogen atom, a C₁ -C₄ alkyl group or a C₁ or C₂ alkoxy group,preferably a hydrogen atom, or a methyl or methoxy group, morepreferably a hydrogen atom or a methyl group, and most preferably amethyl group;

n is 1 or 2, preferably 1;

Y is an oxygen atom;

Z is an oxygen atom or an imino group, most preferably an oxygen atom;and

W is a --CH₂ -- or >CIO group, preferably a --CH₂ -- group.

Referring to the general Formula II, the substituents may be any from 1to 3 selected from nitro, amino, alkylamino, dialkylamino, alkoxy, halo,alkyl, or hydroxy, the aromatic acyl group may be benzoyl and naphthoyl.The alkyl group R₁₁ may be a straight chain or branched alkyl of 1 to 10carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, t-butyl, n-pentyl, i-pentyl, n-hexyl, n-heptyl, n-octyl,n-nonyl, and n-decyl; the cycloalkyl group R₁₁ may be a cycloalkyl groupof 3 to 7 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl,and cycloheptyl; and the phenylalkyl group R₁₁ may be a phenylalkylgroup of 7 to 11 carbon atoms such as benzyl and phenethyl. As examplesof the heterocyclic group R₁₁ may be mentioned 5- or 6-membered groupseach including 1 or 2 hetero-atoms selected from among nitrogen, oxygen,and sulfur, such as pyridyl, thienyl, fluryl, thiazolyl, etc. When R₁₁is ##STR16## the lower alkyls R₁₃ and R₁₄ may each be a lower alkyl of 1to 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, andn-butyl. When R₁₃ and R₁₄ are combined to each other to form a 5- or6-membered heterocyclic group as taken together with the adjacent Natom, ie, in the form of ##STR17## this heterocyclic group may furtherinclude a heteroatom selected from among nitrogen, oxygen, and sulfur asexemplified by piperidino, morpholino, pyrrolidino, and piperazino. Thelower alkylene group R₁₂ may contain 1 to 3 carbon atoms and thus maybe, for example, methylene, ethylene, or trimethylene. The bond R₁₂ isequivalent to the symbol "--", ".", or the like which is used inchemical structural formulas, and when R₁₂ represents such a bond, thecompound of general Formula II is represented by the following generalFormula II (a) ##STR18## Thus, when R₁₂ is a bond, the atoms adjacentthereto on both sides are directly combined together. As examples of thelower alkyls L₁ and L₂, there may be mentioned lower alkyl groups of 1to 3 carbon atoms, such as methyl and ethyl. The alkylene group formedas L₁ and L₂ are joined together is a group of the formula --(CH₂)_(n)-- [where n is an integer of 2 to 6]. The cycloalkyl, phenylalkyl,phenyl, and heterocyclic groups mentioned above, as well as saidheterocyclic group ##STR19## may have 1 to 3 substituents in optionalpositions on the respective rings. As examples of such substituents maybe mentioned lower alkyls (eg, methyl, ethyl, etc.), lower alkoxy groups(eg, methoxy, ethoxy, etc.), halogens (eg, chlorine, bromine, etc.), andhydroxyl. The case also falls within the scope of the general Formula IIthat an alkylenedioxy group of the formula --O--(CH₂)_(m) --O-- [is aninteger of 1 to 3], such as methylenedioxy, is attached to the twoadjacent carbon atoms on the ring to form an additional ring.

The preferred compounds of Formula III are those wherein R₁₅ and R₁₆ areindependently hydrogen, lower alkyl containing 1 to 6 carbon atoms,alkoxy containing 1 to 6 carbon atoms, halogen, ethynyl, nitrile,trifluoromethyl, vinyl, or nitro; n is 1 or 2 and the pharmaceuticallyacceptable salts thereof.

Preferred in Formula IV are compounds wherein the dotted line representsno bond, particularly wherein D is CO or CHOH. More preferred arecompounds wherein V is --CH═CH--, --CH═N-- or S and n is 2, particularlythose compounds wherein X is O and Y is N, X is S and Y is N, X is S andY is CH or X is --CH═N-- and Y is CH. In the most preferred compounds Xis O or S and Y is N forming an oxazol4yl, oxazol5yl, thiazol4yl, orthiazol5yl group; most particularly a 2[(2thienyl), (2furyl), phenyl, orsubstituted phenyl]5methyl-4-oxazolyl group.

The preferred compounds in Formula V are:

a) those wherein the dotted line represents no bond, A and B are eachCH, X₁ is CO, n is 0, R₁₉ is hydrogen, Z₂ is CH₂ CH₂ or CHICH and X₃ ishydrogen, particularly when X₂ is hydrogen, 2-methoxy, 4-benzyloxy, or4-phenyl;

b) those wherein A and B are each CH, X₁ is S or SO₂, n is 0, R₁₉ ishydrogen, Z₂ is CH₂ CH₂ and X₃ is hydrogen, particularly when X₂ ishydrogen or 4-chloro.

A preferred group of compounds is that of Formula VI wherein R₂₃ is (C₁-C₆)alkyl, (C₃ -C₇)cycloalkyl, phenyl, halophenyl, or (C₁-C₆)alkylphenyl. Especially preferred within this group are thecompounds where R₂₃ is phenyl, methylphenyl, fluorophenyl, chlorophenyl,or cyclohexyl.

When used herein with regard to Formulas VII through X, the term "aryl"includes phenyl and naphthyl, suitably phenyl, optionally substitutedwith up to 5, preferably up to 3, groups selected from halogen, alkyl,phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy,alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonylgroups.

The term "halogen" refers to fluorine, chlorine, bromine, and iodine;preferably chlorine.

The terms "alkyl" and "alkoxy" relate to groups having straight orbranched carbon chains, containing up to 12 carbon atoms.

Suitable alkyl groups are C₁₋₁₂ alkyl groups, especially C₁₋₆ alkylgroups, eg, methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, ortert-butyl groups.

Suitable substituents for any alkyl group include those indicated abovein relation to the term "aryl".

Suitable substituents for any heterocyclyl group include up to 4substituents selected from the group consisting of alkyl, alkoxy, aryl,and halogen or any 2 substituents on adjacent carbon atoms, togetherwith the carbon atoms to which they are attached, may form an arylgroup, preferably a benzene ring, and wherein the carbon atoms of thearyl group represented by the said 2 substituents may themselves besubstituted or unsubstituted.

Specific examples of compounds of the present invention are given in thefollowing list:

(+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione;

4-(2-naphthylmethyl)- 1,2,3,5-oxathiadiazole-2-oxide;

5-[4-[2-[N-(benzoxazol-2-yl)-N-methylamino]ethoxy]benzyl]-5-methylthiazolidine-2,4-dione;

5-[4-[2-[2,4-dioxo-5-phenylthiazolidin-3-yl)ethoxy]benzyl]thiazolidine-2,4-dione;

5-[4-[2-[N-methyl-N-(phenoxycarbonyl)aminolethoxy]-benzyl]thiazolidine-2,4-dione;

5-[4-(2-phenoxyethoxy)benzyl]thiazolidine-2,4-dione;

5-[4-[3-(5-methyl-2-phenyloxazol-4-yl)propionyl]benzyl]thiazolidine-2,4-dione;

5-[4-[2-(4-chlorophenyl)ethylsulfonyl]benzyl]thiazolidine-2,4-dione;

5-[4-[3-(5-methyl-2-phenyloxazol-4-yl)propionyl]benzyl]thiazolidine-2,4-dione;

5-(4-[2-(N-methyl-N-(2-pyridyl)amino)-ethoxy]benzyl)2,4-thiazolidinedione;

5-[p-[1-methylcyclohexyl)methoxyl]benzyl]-2,4-thiazolidinedione(Ciglitazone);

5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione(Pioglitazone);

5-[p-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]benzyl]-2,4-thiazolidinedione(Darglitazone);

5-[[(2R)-2-benzyl-6-chromanyl]methyl]-2,4-thiazolidinedione(Englitazone); and

5-(4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl)-2,4-thiazolidine(Rosiglitazone).

As defined herein, "complications of NIDDM" is referred to ascardiovascular complications or several of the metabolic and circulatorydisturbances that are associated with hyperglycemia, eg, insulinresistance, hyperinsulinemia and/or hyperproinsulinemia, delayed insulinrelease, dyslipidemia, retinopathy, peripheral neuropathy, nephropathy,and hypertension.

The compounds of Formulas I through X are capable of further formingpharmaceutically acceptable base salts.

The compounds of Formulas I through X are capable of further formingboth pharmaceutically acceptable acid addition and/or base salts. All ofthese forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds ofFormulas I through X include salts derived from nontoxic inorganic acidssuch as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic,hydriodic, hydrofluoric, phosphorous, and the like, as well as the saltsderived from nontoxic organic acids, such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and aromaticsulfonic acids, etc. Such salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, nitrate, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate,propionate, caprylate, isobutyrate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,maleate, tartrate, methanesulfonate, and the like. Also contemplated aresalts of amino acids such as arginate and the like and gluconate,galacturonate, n-methyl glucamine (see, for example, Berge S. M. et al.,"Pharmaceutical Salts," Journal of Pharmaceutical Science,1977;66:1-19).

The acid addition salts of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formmay be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner or as above. The free baseforms differ from their respective salt forms somewhat in certainphysical properties such as solubility in polar solvents, but otherwisethe salts are equivalent to their respective free base for purposes ofthe present invention.

Pharmaceutically acceptable base addition salts are formed with metalsor amines, such as alkali and alkaline earth metals or organic amines.Examples of metals used as cations are sodium, potassium, magnesium,calcium, and the like. Examples of suitable amines areN,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,dicyclohexylamine, ethylenediamrine, N-methylglucamine, and procaine(see, for example, Berge S. M. et al., "Pharmaceutical Salts," Journalof pharmaceutical Science, 1977;66:1-19).

The base addition salts of said acidic compounds are prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner. The free acid formmay be regenerated by contacting the salt form with an acid andisolating the free acid in the conventional manner or as above. The freeacid forms differ from their respective salt forms somewhat in certainphysical properties such as solubility in polar solvents, but otherwisethe salts are equivalent to their respective free acid for purposes ofthe present invention.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

Certain of the compounds of the present invention possess one or morechiral centers and each center may exist in different configurations.The compounds can, therefore, form stereoisomers. Although these are allrepresented herein by a limited number of molecular formulas, thepresent invention includes the use of both the individual, isolatedisomers and mixtures, including racemates, thereof. Where stereospecificsynthesis techniques are employed or optically active compounds areemployed as starting materials in the preparation of the compounds,individual isomers may be prepared directly; on the other hand, if amixture of isomers is prepared, the individual isomers may be obtainedby conventional resolution techniques, or the mixture may be used as itis, without resolution.

Furthermore, the thiazolidene part of the compound of Formulas I throughX can exist in the form of tautomeric isomers. All of the tautomers arerepresented by Formulas I through X, and are intended to be a part ofthe present invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term "preparation" is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsules, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 100 mg preferably 0.5 mg to 100 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use in the treatment of at risk populations such as thosewith impaired glucose tolerance, to prevent or delay the onset of NIDDMand complications arising therefrom, the compounds utilized in thepharmaceutical methods of this invention are administered along with apharmaceutically acceptable carrier at the initial dosage of about 0.01mg to about 20 mg per kilogram daily. A daily dose range of about 0.01mg to about 10 mg per kilogram is preferred. The dosages, however, maybe varied depending upon the requirements of the patient, the severityof the condition being treated, and the compound being employed.Determination of the proper dosage for a particular situation is withinthe skill of the art. Generally, treatment is initiated with smallerdosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day, if desired.

The following nonlimiting examples illustrate the inventors' preferredmethods for preparing the compounds of the invention.

The compounds of Formulas I through X are valuable agents in returningan individual to a state of glucose tolerance and therefore preventingor delaying the onset of NIDDM. Tests were conducted which showed thatcompounds of Formulas I through X possess the disclosed activity. Thetests employed on the compounds of Formulas I through X were performedby the following study.

EXAMPLE 1

A study will be performed to determine the effect of troglitazone((+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione)on insulin resistance and androgen levels in PCOS women. Sincehyperandrogenism results in chronic anovulation and hirsutism,decreasing androgen levels may improve hirsutism and even restore normalovulatory menstrual function in PCOS women. The specific aim of thestudy will be to determine the effects of improved insulin sensitivityand decreased insulin levels secondary to troglitazone treatment oncirculating androgen and gonadotropin levels in PCOS women.

I. SUBJECTS

A. General Selection Criteria. A total of 30 women will be studied. Allsubjects will be in excellent health, between the ages of 18-45 years,and euthyroid. There will be no history of cardiorespiratory, hepatic,or renal dysfunction. No subject will be taking any medications known toaffect reproductive hormone levels or carbohydrate metabolism for atleast 1 month prior to study, with the exception of oral contraceptives,which will be discontinued 3 months prior to study. Obesity will bedefined as body mass index (BMI: wt (kg)/hr² (m) of ≧27 kg/m², non-obesepatients will have a BMI of ≧25 kg/m².

B. Selection criteria for PCOS. The diagnosis of PCOS will requirebiochemically documented hyperandrogenism (serum levels of testosterone,biologically available testosterone, and/or androstenedione two standarddeviations or more above the control mean), chronic anovulation (<6menses/year or dysfunctional uterine bleeding), and polycystic ovariespresent on vaginal ovarian ultrasound. These are the least controversialcriteria for diagnosis for PCOS. The LH:FSH ratio and hirsutism will notbe used as selection criteria. Androgen secreting tumors, Cushing'sSyndrome, and late-onset congenital adrenal hyperplasia will be excludedby appropriate tests in all women. Women with hyperprolactinemia will beexcluded because of the possible effect of hyperprolacticemia on insulinsensitivity.

C. Disqualification Criteria

1. Pregnancy

2. Intercurrent medical illness

3. Hepatic or renal dysfunction

4. Hemoglobin<11 gm/dL

5. Weight <50 kg.

II. STUDY PROTOCOL

A. Subject Preparation for All Studies. All testing will be performedduring a period of documented anovulation by plasma progesterone levelsin PCOS women. Subjects will consume a 55% carbohydrate, 30% fat, 15%protein weight maintaining diet for 3 days prior to testing and alltesting will be done in the post-absorptive state after 10-12 hoursfast.

B. Protocol

1. Visit1--Day 1. A complete history and physical examination will beperformed and blood for a complete blood count, electrolytes, thyroidfunction (thyroid profile with TSH level), renal chemistries and liverfunction will be obtained. Blood for testosterone (T), biologicallyavailable T (μT), LH, FSH, dehydroepiandrosterone sulfate (DHEAS),androstenedione (A), sex hormone binding globulin (SHBG), estrone (E₁),estradiol (E₂), insulin, and C-peptide levels will be obtained. A 75 gglucose load will be ingested in the morning after a 10-12 hour fast,and glucose and insulin levels will be obtained every 30 minutes for 2hours. All PCOS women will have fasting insulin levels ≧15 μ/mL and mayhave impaired glucose tolerance by WHO criteria. No subject, however,will have diabetes mellitus.

    ______________________________________                                        WHO Diagnostic Criteria                                                       Serum                                                                         Glucose                                                                       mg/dL                                                                         (mmol/L)                                                                             Normal      IGT           Diabetes                                     ______________________________________                                        Fasting                                                                              <140   (<7.8)   <140   (<7.8) ≧140                                                                          (≧7.8)                     2 hour <140   (<7.8)   140-199                                                                              (7.8-11.1)                                                                           ≧200                                                                         (≧11.1)                     ______________________________________                                    

2. Visit 1--Day 2. A frequently sampled intravenous glucose tolerancetest (FSIGT) will be performed. Basal blood samples will be collected at-15,-10,-5, and -1 minute. Glucose (300 mg/kg) will be injected as an IVbolus at time 0 minute and tolbutamide (500 mg) will be injected at 20minutes. Blood samples will be taken at 2, 3, 4, 5, 8, 10, 12, 14, 16,19, 22, 23, 24, 25, 27, 30, 40, 50, 60, 70, 90, 100 minutes, and every20 minutes thereafter until 240 minutes for glucose and insulin levels.

3. Troglitazone therapy. Troglitazone will be started after Visit 1, Day2, when a urine pregnancy test will be documented to be negative.Troglitazone will be administered in a double-blind randomized trial oftwo dose levels: 200 mg/day and 400 mg/day. Subjects will be randomlyassigned to one of the two daily doses of troglitazone. All women willtake two pills: either two 200 mg pills or a 200 mg pill and a placebopill. There will be 15 subjects in each of the two treatment groups.Troglitazone will be administered as a single daily dose with breakfast.

4. Visits 2 and 3. Subjects will return monthly. Blood will be obtainedevery 10 minutes×3 and the plasma pooled for assay of T, μT, A, DHEAS,SHBG, E₂, E₁, LH, and FSH levels. Insulin and glucose levels basally and2 hours after 75 g glucose will be determined.

5. Visit 4. The studies performed at Visit 1 will be repeated. Subjectswill be instructed to return all unused supplies or empty bottles at thetime of each visit to ensure compliance. Details related to patientdosage and compliance will be recorded on the case report form.

III. STATISTICAL ANALYSIS

Each subject will serve as her own control, and the data will beanalyzed by paired t-test. Differences in treatment vs baseline hormonelevels and parameters of insulin action will be compared between the twodose groups by unpaired t-tests. Repeated measures of analysis ofvariance will be performed to determine changes over time. Logtransformation of the data will be performed when necessary to achievehomogeneity of variance. This is a pilot study and 15 PCOS women eachwill be examined at two dose levels of troglitazone.

IV. HUMAN SUBJECTS

A. Risks

1. Blood Withdrawal. All subjects will have normal a complete bloodcount and hemoglobin levels >11 mg/dL. No subject will have >500 MLblood drawn in 24-hour period and >1000 mL blood drawn over 12-weekperiod.

2. FSIGT. There is a small risk of hypoglycemia during FSIGT, and thetest will be terminated immediately by administration of 50% dextrose ifsigns or symptoms of severe hypoglycemia develop. There is a small riskof allergy to tolbutamide; the drug will not be given to any subjectwith a history of allergy to sulfa drugs or sulfonylureas.

3. Troglitazone. The major side effects of troglitazone are nausea,peripheral edema, and abnormal liver function. Other reported adverseevents include dyspnea, headache, thirst, gastrointestinal distress,insomnia, dizziness, incoordination, confusion, fatigue, pruritus, rash,alterations in blood cell counts, changes in serum lipids, acute renalinsufficiency, and dryness of the mouth. Additional symptoms that havebeen reported, for which the relationship to troglitazone is unknown,include palpitations, sensations of hot and cold, swelling of bodyparts, skin eruption, stroke, and hyperglycemia.

4. Disqualification Criteria. Subjects will be disqualified if they willdevelop one or more of the following: HB <11 gm/dL, wt <50 kg, abnormalhepatic or renal chemistries, hypertension, pregnancy, significantillnesses, or excessive bleeding.

    __________________________________________________________________________           History Physical                                                                      EKG                                                                              Pregnancy Test                                                                       Chemistry.sup.a                                                                     Hormones.sup.b                                                                      OGTT                                                                              FSIGT                                                                             Timing                           __________________________________________________________________________    Visit 1 - Day 1                                                                      X       X         X     X     X       Baseline                         Visit 1 - Day 2   X                      X   Baseline                         Visit 2                                                                              X          X            X     X       1 month                          Visit 3                                                                              X          X            X     X       2 months                         Visit 4 - Day 1                                                                      X       X         X     X     X       3 months                         Visit 4 - Day 2   X                      X   3 months                         __________________________________________________________________________     .sup.a Chemistry  Complete blood count with differential, electrolytes,       liver function, renal function, thyroid profile with TSH level                .sup.b Hormones  T, μT, LH, FSH, DHEAS, SHBG, P, A, E.sub.2, E.sub.1,      insulin, Cpeptide levels                                                 

EXAMPLE 2

Thiazolidinediones have been shown to increase insulin sensitivity ininsulin-resistant, non-diabetic and diabetic animals and in humans withNIDDM. Several thiazolidinediones are undergoing testing in the U.S.,including studies of proglitizone in fructose-fed rats and obese rhesusmonkeys. The drugs appear to improve insulin sensitivity in skeletalmuscle and liver, major sites of insulin resistance in NIDDM. Inresponse to the increased insulin sensitivity, which has been in therange of 40-100% above pretreatment levels, pancreatic B-cells appear todown-regulate insulin secretion, so that hyperinsulinemia is reduced andhypoglycemia is not a risk. Of the possible pharmacologicalinterventions, thiazolidinediones appear well-suited for testing in theprevention of NIDDM in patients whose underling insulin resistance isthought to lead to B-cell decompensation and diabetes. Therefore, it isproposed to test the effects of a thiazolidinedione that has been shownto increase insulin sensitivity in people with NIDDM, on insulinsensitivity and NIDDM rates in our very high-risk patients with recentGDM.

In particular, it is proposed to test the effects of the agent,troglitazone, that has been shown to enhance insulin-mediated glucosedisposal in humans. While not wishing to be bound by theory, if thehypothesis is correct, troglitazone will maintain insulin action at alevel which is commensurate with B-cell reserve in some, and perhapsmany subjects, thereby preventing or delaying the development of NIDDM.

The demonstration that treatment with troglitazone will reduce the rateof NIDDM in patients with GDM will have important clinical andbiological significance. The clinical significance is the obviouspotential for treatment of GDM patients to prevent or delay overtdiabetes and its long-term complications. The choice of an agent thatimproves insulin action may not only reduce the risk of diabeticcomplications that clearly are related to chronic metabolicdecompensation (ie, retinopathy, hephropathy, and neuropathy), but alsomay reduce the risk of cardiovascular complications such as hypertensionand atherosclerosis, that have been associated with insulin resistanceand hyperinsulinemia. The biological significance of a reduced rate ofdiabetes during treatment with troglitazone will depend to some extenton the effects of the drug on insulin action.

To test the hypothesis that interventions to improve whole-body insulinsensitivity will reduce the rate of B-cell decompensation and delay orprevent the development of NIDDM, a randomized, double-blind,placebo-controlled trial of troglitazone will be performed. The trialwill be performed among individuals at high risk for NIDDM such as womenwith a history of GDM. In particular, because the age-adjustedprevalence rates of NIDDM among Hispanic women aged 24-64 years havebeen reported to be 8-11%, rates which are 2-3 times those ofnon-Hispanic whites in the US, the test will be performed among Hispanicwomen.

I. OVERVIEW OF STUDY DESIGN

Hypothesis: Troglitazone will improve insulin sensitivity and delay orprevent NIDDM in Latino women with a history of GDM who are at very highrisk for NIDDM.

Patients: ˜230 Hispanic women with recent GDM and a glucose tolerancetest at 6-12 weeks postpartum indicating a very high risk of developingNIDDM within 3-5 years (ie, total glucose area >16.3 gm·min/dL).

Procedures:

1. Measure whole-body insulin sensitivity (minimal model S₁) atbaseline.

2. Randomize to drug or placebo (double-blind design).

3. Measure insulin sensitivity after 4 and 24 months on treatment.

4. Follow for development of NIDDM:

a. Fasting glucose at 4-month intervals

b. Oral glucose tolerance test annually

c. Mean follow-up of 36 months.

Analysis:

1. Between group (drug and placebo) comparison of cumulative NIDDM ratesusing life table methods:

a) by intent-to-treat

b) by response-to-therapy.

2. Between group comparison of 4-month changes in S₁ using 2-groupt-test; between group changes in S₁ over time using repeated measuresANOVA.

3. Within and between group analysis of factors associated with anyreduction in NIDDM rate using Cox proportional hazards regressionanalysis.

II. INTERVENTION TRIAL: SUBJECT SELECTION AND ENROLLMENT

A. Inclusion and Exclusion Criteria

INCLUSION: Age 18-45 years, recent GDM by the National Diabetes DataGroup criteria, Diabetes, 1979;29:1039-1057, singleton pregnancy,Mexican-American or Central-American (self-declared ethnicity); bothparents and 3/4 grandparents of Mexican or Central American heritage,residence within 60 minutes of LAC Medical Center, 6-12 week postpartumOGTT glucose area >16.3 gm·min/dL.

EXCLUSION: Plans for pregnancy within 4 years, medical illness requiringchronic medications that alter glucose tolerance or that will preclude3-4 years of follow-up (eg, malignancy, HIV infection), illicit drugabuse, inability to give informed consent.

III. SPECIFIC PROCEDURES

A. OGTT

1. Procedure: Sitting subjects will have an indwelling antecubitalvenous catheter placed in the morning after a 10-12 hour fast. At least30 minutes later, dextrose (75 g) will be given orally over 5 minutes.Blood will be drawn at -10, 30, 60, 90, and 120 minutes from the startof the dextrose ingestion.

2. Interpretation: OGTTs plasma glucose concentrations will beinterpreted according to National Diabetes Data Group criteria.

3. Risks: Limited to those of an intravenous line (pain, infection,bruising/bleeding at site), nausea at the time of dextrose ingestion,and phlebotomy (15 mL blood).

B. IVGTT

1. Procedure: After an overnight fast, subjects will be placed atbedrest and will have bilateral antecubital venous catheters placed. Atleast 30 minutes later, a basal blood sample will be drawn and dextrose(300 mg/kg body weight) will be given intravenously over 1 minute. Anintravenous injection of tolbutamide (3 mg/kg) will be given 20 minutesafter the dextrose injection. Plasma samples will be obtained at 2, 4,8, 14, 19, 22, 30, 40, 50, 70, 100, and 180 minutes after the glucoseinjection and assayed for glucose and insulin.

2. Analysis: Insulin sensitivity will be calculated by computer analysisof the glucose and insulin patterns during the IVGTT.

3. Risks: Hypoglycemia is a potential complication following tolbutamideinjection. However, tolbutamide is injected when the plasma glucose ishigh, so that hypoglycemia is unusual. It has never been observed inover 50 IVGTTs in Hispanic women using the 3 mg/kg tolbutamide dose.Nonetheless, patients will be observed for symptoms of hypoglycemia andstop the test if symptomatic hypoglycemia (<60 mg/dL) occurs. Risks ofintravenous lines and phlebotomy (total=39 mL) are minimal. Persons witha hematocrit <33% will not be studied with the IVGTT.

C. Body Morphometry

1. Procedures: Body weight will be measured on a standard beam balance(subjects lightly clothed, without shoes). Height will be measured witha statometer. Waist circumference will be measured at the minimumcircumference between the thorax and the iliac crest. Hip circumferencewill be measured at the level of the maximum posterior protrusion of thebuttocks.

2. Interpretation: Body mass index will be calculated as: [weight inkg]/[height in meters] and used as a surrogate for measures ofadiposity. The ratio of the waist circumference to the hip circumferencewill be calculated as a measure of fat distribution. Each measure willbe tested as a predictive feature for NIDDM and for any effects oftherapy on NIDDM risk.

3. Risks: None.

D. Blood Pressure

Blood pressure will be measured in triplicate in sitting (×5 minutes)patients with an aeriod sphygmomanometer. First and fourth Korotkoffsounds will be used to determine systolic and diastolic BP. There are norisks associated with the procedure.

E. Assays

1. Insulin: Insulin is measured in plasma with a charcoal precipitationradioimmunoassay using human insulin standard, guinea pig anti-porcineinsulin antibodies, and tyrosine A-19 iodoinsulin purchased fromNovo-Nordisk. Quality control will be maintained. RIA has a meaninterassay coefficient of variation of 12% at 7±3 μU/mL and 7% at 32±6μU/mL, based on pooled plasma samples stored at -70° C. over a period of12 months.

2. Glucose: Glucose will be measured in duplicate by glucose oxidase(Beckman Glucose Analyzer II).

The present invention may be embodied in other specific forms withoutdeparting from its spirit or essential characteristics. The describedembodiments are to be considered in all respects only as illustrativeand not restrictive. The scope of the invention is, therefore, indicatedby the appended claims rather than by the foregoing description. Allchanges which come within the meaning and range of equivalency of theclaims are to be embraced within their scope.

What is claimed is:
 1. A method of treating anovulation, the methodcomprising administering to a patient suffering from anovulation atherapeutically effective amount of(+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione(Troglitazone).
 2. A method of treating anovulation, the methodcomprising administering to a patient suffering from anovulation atherapeutically effective amount of5-[p-[1-methylcyclohexyl)methoxyl]benzyl]-2,4-thiazolidinedione(Ciglitazone),5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione(Pioglitazone),5-[p-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]benzyl]-2,4-thiazolidinedione(Darglitazone), or5-[[(2R)-2-benzyl-6-chromanyl]methyl]-2,4-thiazolidinedione(Englitazone).
 3. A method of treating anovulation, the methodcomprising administering to a patient suffering from anovulation atherapeutically effective amount of5-(4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl)-2,4-thiazolidinedione(Rosiglitazone).
 4. A method of treating hyperandrogensim, the methodcomprising administering to a patient suffering from hyperandrogensim atherapeutically effective amount of(+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione(Troglitazone).
 5. A method of treating hyperandrogensim, the methodcomprising administering to a patient suffering from hyperandrogensim atherapeutically effective amount of5-[p-[1-methylcyclohexyl)methoxyl]benzyl]-2,4-thiazolidinedione(Ciglitazone),5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione(Pioglitazone),5-[p-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]benzyl]-2,4-thiazolidinedione(Darglitazone), or5-[[(2R)-2-benzyl-6-chromanyl]methyl]-2,4-thiazolidinedione(Englitazone).
 6. A method of treating hyperandrogensim, the methodcomprising administering to a patient suffering from hyperandrogensim atherapeutically effective amount of5-(4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl)-2,4-thiazolidinedione(Rosiglitazone).
 7. A method of treating hirsutism, the methodcomprising administering to a patient suffering from hirsutism atherapeutically effective amount of(+)-5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione(Troglitazone).
 8. A method of treating hirsutism, the method comprisingadministering to a patient suffering from hirsutism a therapeuticallyeffective amount of5-[p-[1-methylcyclohexyl)methoxyl]benzyl]-2,4-thiazolidinedione(Ciglitazone),5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione(Pioglitazone),5-[p-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]benzyl]-2,4-thiazolidinedione(Darglitazone), or 5-[[(2R)-2-benzyl-6-chromanyl]methyl]-2,4-thiazolidinedione (Englitazone).9. A method of treating hirsutism, the method comprising administeringto a patient suffering from hirsutism a therapeutically effective amountof5-(4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl)-2,4-thiazolidinedione(Rosiglitazone).